RESUMEN
BACKGROUND AND OBJECTIVE: Immunosuppressive therapy (IST) is the first choice for severe aplastic anemia (SAA) patients with hematopoietic stem cell transplantation (HSCT) limitation, and the main factor limiting its efficacy is too few residual hematopoietic stem/progenitor cells (HSPC). Eltrombopag (EPAG), as a small molecule thrombopoietin receptor agonist, can stimulate the proliferation of residual HSPC and restore the bone marrow hematopoietic function of patients. In recent years, many studies have observed the efficacy and safety of IST combined with EPAG in the treatment of SAA, but the results are still controversial. The aim of this study is to systematically evaluate the efficacy and safety of IST combined with or without EPGA in the treatment of SAA. METHODS: We conducted a systematic review of all relevant literature published up to January 19, 2024. Pooled odds ratio (OR) was calculated to compare the rates, along with 95% confidence intervals (CI) and p value to assess whether the results were statistically significant by Review Manager 5.4.1. The p values for the interactions between each subgroup were calculated by Stata 15.1. The Newcastle-Ottawa Scale and the Cochrane bias risk assessment tools were respectively used to evaluate the quality of the literature with cohort studies and randomized controlled trials. The Review Manager 5.4.1 and Stata 15.1 were used to assess bias risk and perform the meta-analysis. RESULTS: A total of 16 studies involving 2148 patients were included. The IST combined with the EPAG group had higher overall response rate (ORR) than the IST group at 3 months (pooled OR = 2.10, 95% CI 1.58-2.79, p < 0.00001) and 6 months (pooled OR = 2.13, 95% CI 1.60-2.83, p < 0.00001), but the difference between the two groups became statistically insignificant at 12 months (pooled OR = 1.13, 95% CI 0.75-1.72, p = 0.55). The results of complete response rate (CRR) (pooled OR at 3 months = 2.73, 95% CI 1.83-4.09, p < 0.00001, 6 months = 2.76, 95% CI 2.08-3.67, p < 0.00001 and 12 months = 1.38, 95% CI 0.85-2.23, p = 0.19) were similar to ORR. Compared with the IST group, the IST combined with the EPAG group had better overall survival rate (OSR) (pooled OR = 1.70, 95% CI 1.15-2.51, p = 0.008), but there were no statistically significant differences in event-free survival rate (EFSR) (pooled OR = 1.40, 95% CI 0.93-2.13, p = 0.11), clonal evolution rate (pooled OR = 0.68, 95% CI 0.46-1.00, p = 0.05) and other adverse events between the two groups. The results of subgroup analysis showed that different ages were a source of heterogeneity, but different study types and different follow-up times were not. Moreover, all p-values for the interactions were greater than 0.05, suggesting that the treatment effect was not influenced by subgroup characteristics. CONCLUSION: EPAG added to IST enables patients to achieve earlier and faster hematologic responses with a higher rate of complete response. Although it had no effect on overall EFSR, it improved OSR and did not increase the incidence of clonal evolution and other adverse events.
Asunto(s)
Anemia Aplásica , Hidrazinas , Inmunosupresores , Pirazoles , Humanos , Inmunosupresores/uso terapéutico , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/epidemiología , Terapia de Inmunosupresión , Benzoatos/uso terapéutico , Respuesta Patológica Completa , Resultado del TratamientoRESUMEN
BACKGROUND: Cerebral ischemia/reperfusion injury (IRI) is pathologically associated with protein damage. The flavonoid fisetin has good therapeutic effects on cerebral IRI. However, the role of fisetin in regulating protein damage during cerebral IRI development remains unclear. This study investigated the pharmacological effects of fisetin on protein damage during cerebral IRI progression and defined the underlying mechanism of action. METHODS: In vivo and in vitro models of cerebral IRI were established by middle cerebral artery occlusion/reperfusion (MACO/R) and oxygen-glucose deprivation/reperfusion (OGD/R) treatment, respectively. Triphenyl tetrazolium chloride staining was performed to detect cerebral infarct size, and the modified neurologic severity score was used to examine neurological deficits. LDH activity and protein damage were assessed using kits. HT22 cell vitality and apoptosis were examined using CCK-8 assay and TUNEL staining, respectively. Interactions between Foxc1, Ubqln1, Sirt1, and Ezh2 were analyzed using CoIP, ChIP and/or dual-luciferase reporter gene assays. RESULTS: Fisetin alleviated protein damage and ubiquitinated protein aggregation and neuronal death caused by MCAO/R and OGD/R. Ubqln1 knockdown abrogated the inhibitory effect of fisetin on OGD/R-induced protein damage, ubiquitinated protein aggregation, and neuronal death in HT22 cells. Further experiments demonstrated that Foxc1 functions as a transcriptional activator of Ubqln1 and that Sirt1 promotes Foxc1 expression by deacetylating Ezh2 and inhibiting its activity. Furthermore, Sirt1 knockdown abrogated fisetin-mediated biological effects on OGD/R-treated HT22 cells. CONCLUSION: Fisetin improved proteostasis during cerebral IRI by regulating the Sirt1/Foxc1/Ubqln1 signaling axis. Our findings strongly suggest that fisetin-mediated inhibition of protein damage after ischemic stroke is a part of the mechanism through which fisetin is neuroprotective in cerebral IRI.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Proteínas Relacionadas con la Autofagia , Isquemia Encefálica , Flavonoles , Factores de Transcripción Forkhead , Proteostasis , Daño por Reperfusión , Sirtuina 1 , Apoptosis , Isquemia Encefálica/tratamiento farmacológico , Flavonoles/farmacología , Flavonoles/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Agregado de Proteínas , Proteostasis/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Sirtuina 1/metabolismo , Masculino , Animales , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción Forkhead/metabolismo , Proteínas Relacionadas con la Autofagia/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismoRESUMEN
The present study aimed to compare the efficacy of combination therapy with venetoclax and azacitidine with that of azacytidine monotherapy in the treatment of acute myeloid leukemia (AML). The Web of Science, PubMed, Embase, The Cochrane Library, Weipu Database, Wanfang Digital Periodicals, Sinomed, China National Knowledge Infrastructure, ProQuest Dissertations and Theses and Cumulative Index to Nursing and Allied Health Literature were searched for publications on the treatment of AML with venetoclax combined with azacitidine or with azacitidine monotherapy. A total of 5,271 relevant studies were retrieved, of which 10 were included. Literature quality was evaluated according to the Cochrane systematic review methodology, and data were extracted for meta-analysis using Review Manager 5.4. The combination of venetoclax and azacitidine demonstrated greater overall efficacy than azacitidine monotherapy for AML treatment. Notably, combination therapy resulted in a higher frequency of complete remission. By contrast, combined treatment and monotherapy showed no significant differences in partial remission, whereas there was a statistically significant decrease in the frequency of no remission in the combination therapy group compared with in the monotherapy group. The results also revealed a significantly higher incidence of adverse reactions when venetoclax and azacitidine were combined in the treatment of AML compared with the observed rates in response to azacitidine monotherapy. Moreover, subgroup analyses showed that no statistically significant differences were observed between the two groups regarding adverse events, including hypokalemia and liver insufficiency. In conclusion, the combination of venetoclax and azacitidine was more effective than azacitidine alone, and had a good clinical application value in the treatment of AML. Although some adverse reactions occurred in response to the combination therapy, they did not significantly affect the prognosis of AML. To better evaluate the efficacy and safety of this treatment regimen, multicenter clinical studies with larger sample sizes are required.